CASE REPORT

Waldenstrom's MacroglobulinaemiaPresenting as DemyelinatingPolyradiculoneuropathy

SAW Fadilah, MMed*, A A Raymond, MD **, I Najihah, MBBS **, S K Cheong, FRCPA*

"Division of Haematology and Stem Cell Transplantation, **Division of Neurology, Faculty of Medicine, UniversitiKebangsaan Malaysia(UKM), ]alan Yaacob, 56000 Kuala Lumpur

Introduction

WM is an unusual low-grade lymphoplasmacyticlymphoma characterised by proliferation ofmalignant lymphocytoid cells in the bone marrowand lymph nodes that secretes monoclonal IgM.WM typically .affects elderly men who usuallypresent with systemic symptoms of fatigue,anaemia, bleeding and hyperviscosity. Peripheralneuropathy occurs in approximately one-third ofpatients with WM. Polyneuropathy associatedwith WM is usually of gradual onset, symmetrical

and predominantly sensory!. However, in thepresent case, the associated polyneuropathy wassubacute in onset, progressive and predominantlymotor. This type of neuropathy in patients withWM is presumably very rare.

Case Report

A 78-year-old man was admitted with a three­week history of difficulty in walking. Theweakness initially involved the lower limbs but

This article was accepted: 2 February 2002Corresponding Author: Fadilah S. Abdul Wahid, Mater Medical Research Institute (MMRI), Aubigny Place, Raymond Tee, SouthBrisbane, Queensland 410 1, Australia. email: fabdulwahid@mmri.mater.org.au

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The haemoglobin level was 11.2 g/dl withnormal red cell indices, white cell count 2.3 x

subsequently ascended to involve both upperlimbs. There was no numbness, and no bladderor bowel incontinence. There was no history offever or weight loss.

He had a history of forgetfulness for thepreceding 2 years, and was treated asAlzheimer's disease with donepezil elsewhere.He did not have diabetes mellitus, hypertensionor thyroid disorder. He was a non-smoker andteetotal.

109/1 and platelet count 259 x 109/1. Microscopicexamination of the peripheral blood smearsshowed marked red cell rouleaux formation andleucoerythroblastosis. The erythrocytesedimentation rate (ESR) was 124 mm in the firsthour. The serum total protein level was 88 gil,albumin 28 gil, bilirubin 7 Ilmolll, ALP 83 U/land ALT 14 U/l. The blood glucose, serumelectrolytes, serum creatine kinase and thyroidfunction test 'were normal and the VDRL wasnon-reactive. The bone marrow was heavilyinfiltrated by plasmacytoid lymphoid cells(Figure 1) and most of these cells expressedsurface CD19, CD20 antigens and kappa lightchains. No deposits of amyloid or cryoglobulinwere observed in the trephine biopsyspecimens. Serum protein electrophoresisrevealed a raised IgM-kappa paraprotein level at30.6 (NR: 0.5-2 gil). The serum IgG level was11.26 (NR: 5-14 gil) and IgA 0.78 (NR: 0.5-3 gil).A skeletal survey revealed no lytic lesions. Theserum calcium level was normal. Serum ~2

microglobulin was elevated at 10.5 (NR < 3mg/D. A diagnosis of Waldenstrom'smacroglobulinaemia (WM) was made based ona high level of circulating IgM and bone marrowinfiltration by plasmacytoid lymphocytes. Thecerebrospinal fluid showed a slightly raisedprotein level of' 537 mg/dl, normal glucosecontent and no cells or organisms. Nerveconduction studies disclosed prolonged distalmotor and F-wave latencies, moderatelydiminished motor conduction velocities andreduced amplitudes of the sensory nerve actionpotentials. The findings were consistent with asymmetrical, predominantly motor, predominantlydemyelinating polyradiculoneuropathy. Thepatient received intravenous immunoglobulin(IVIG) at 0.4 g/kg/day for 5 days that resulted inmarked improvement of his symptoms. He wasable to walk with support on discharge. He alsoreceived oral chlorambucil 15 mg daily for oneweek (planned to be repeated every 4 weeks).However, he had two further similarneurological relapses within the next twomonths. He was treated with IVIG during bothepisodes of relapses with a similar favourable

Smear of the bone marrow aspirate(May·Grunwald·Giemsa,x400)showing a plasmacytoid lymphoidcell.

Neurological examination revealed weakness inall four extremities; mainly affecting the distalmuscles (power of grade 3-4 in the muscles ofthe shoulder and hip joints, grade 2-3 in thehands, wrist and ankle joints), and the flexorswere weaker than the extensors. The deeptendon reflexes were absent. Both plantarresponses were flexor. There was no musclewasting, fasciculation or sensory deficit. Thecranial nerves were normal. The lymph nodes,liver and spleen were not enlarged. Examinationof other systems was unremarkable.

Fig. 1:

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Waldenstrom's Macroglobulinaemia Presenting as Demyelinating Polyradiculoneuropathy

response. His treatment was changed to 1 g ofintravenous cyclophosphamide andplasmapheresis at 3-weekly intervals. After 3courses of cyclophosphamide andplasmapheresis, the patient had no furtherneurological relapses and the paraprotein levelhad decreased to 8.4 gil.

Discussion

Approximately 10% of patients with peripheralneuropathy of otherwise unknown aetiology havean associated monoclonal gammopathy, andapproximately one third of patients with WMdevelop a chronic, predominantly demyelinatingsensory polyneuropathi. This patient's initialclinical presentation did suggest a diagnosis ofGuillain-Barre Syndrome (GBS), and thepolyneuropathy was subacute in onset andpredominantly motor. This type of neuropathy isuncommon in patients with WM. Sural nervebiopsy findings of patients with M proteins shownerve fibre loss, segmental demyelination, andaxonal degeneration, but nerve biopsy was notperformed in the present case, as it would notdifferentiate benign monoclonal gammopathyfrom malignant plasma cell dyscrasias.Immunocytochemical studies on sural nervebiopsies have shown that the monoclonal IgM(usually of K type) is deposited on the outer layerof the myelin sheath, a sign suggestive of IgManti-myelin antibody activity. IgM M proteins thatbind to myelin-associated glycoprotein (MAG)have been shown to cause demyelinatingperipheral neuropathy. Anti-MAG reactivity isfound in 50% of WM patients with neuropathy!. Inthis case, anti-MAG reactivity was not done, as thetest was not available.

The management of polyneuropathy associatedwith monoclonal gammopathy relies on theadministration of systemic chemotherapy toreduce tumour load and on the application ofplasmapheresis to remove circulating IgM. Theeffectiveness of these treatment modalities

remains uncertain. The most difficult cases to treatare those with peripheral neuropathies associatedwith IgM monoclonal gammopathies. Plasmaexchange, followed by a course of chlorambucilis indicated if the symptoms and signs arepredominantly sensory. For cases with rapidprogression or significant disability, a regimen ofmonthly pulses with cyclophosphamide isrecommended'. In a prospective study, short­term treatment with intermittentcyclophosphamide and prednisone can preventworsening of neuropathy associated withmonoclonal gammopathy of undeterminedsignificance (38%) or lead to amelioration (50%),and a reduction in the M-protein levels 3. Ourpatient was initially treated with IVIG based onthe provisional diagnosis of GBS. However, nostudies have been done so far to prove theeffectiveness of IVIG in the treatment ofpolyneuropathy associated with WM. This patienthad two episodes of neurological relapses with aconsistent favourable response to IVIG,suggesting the efficacy of this treatment, albeit anexpensive one. Subsequent treatment withcyclophosphamide and plasmapheresis resultedin both neurological and haematologicalremission.

This case illustrates the importance ofinvestigating for a paraproteinaemia in elderlypatients who present with a subacute peripheralneuropathy, particularly when it mimics GBS, andin the presence of a high ESR or elevated totalprotein level. It is particularly important torecognise the underlying malignantparaproteinaemia because treatment of thesediseases may result in amelioration of theneuropathy and remission of the underlyingmalignancy. In addition, electrophysiologicalstudies are pivotal in the diagnostic evaluation ofpatients who present with a clinical diagnosis ofperipheral neuropathy, and polyneuropathyassociated with monoclonal gammopathy can betreated effectively with IVIG andcyclophosphamide.

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2. Wicklund MP, Kissel ]T. Paraproteinemicneuropathy. Current Treatment Options inNeurology 2000; 3: 147-56.

3. Notermans NC, Lokhorst HM, Franssen H et al.Intermittent cyclophosphamide and prednisonetreatment of polyneuropathy associated withmonoclonal gammopathy of undeterminedsignificance. Neurology 1996; 47: 1227-33.

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